Infiltration of immune cells to the brain and its relation to the pathogenesis of Alzheimer's and Parkinson's diseases.

The neurovascular unit, composed of vascular endothelium, vascular smooth muscle, extracellular matrix components, pericytes, astrocytes, microglia, and neurons, allows the highly regulated exchange of molecules and the limited trafficking of cells to the brain through coordinated signaling activity. The passage of peripheral immune cells to the brain parenchyma is observed when there is clear damage to the barriers of this neurovascular unit, as occurs in traumatic brain injury. The possibility of leukocyte infiltration to the brain in neurodegenerative conditions has been proposed. In this review, we focus on describing the evidence for peripheral immune cell infiltration to the brain in the two most frequent neurodegenerative diseases: Alzheimer's and Parkinson's diseases. In particular, we address the mechanisms that promote the passage of these cells into the brain under such pathological conditions. We also discuss the relevance of the resulting cellular interactions, which provide evidence that the presence of peripheral immune cells in the brain is a key point in these neurodegenerative diseases.

Increased levels of regulatory T cells and IL-10-producing regulatory B cells are linked to improved clinical outcome in Parkinson's disease: a 1-year observational study.

Whilst the contribution of peripheral and central inflammation to neurodegeneration in Parkinson's disease and the role of the immune response in this disorder are well known, the effects of the anti-inflammatory response on the disease have not been described in depth. This study is aimed to assess the changes in the regulatory/inflammatory immune response in recently diagnosed, untreated PD patients and a year after. Twenty-one PD patients and 19 healthy controls were included and followed-up for 1 year. The levels of immunoregulatory cells (CD4+ Tregs, Bregs, and CD8+ Tregs); classical, nonclassical, and intermediate monocytes, and proinflammatory cells (Th1, Th2, and Th17) were measured by flow cytometry. Cytokine levels were determined by ELISA. Clinical follow-up was based on the Hoehn & Yahr and UDPRS scales. Our results indicate that the regulatory response in PD patients on follow-up was characterized by increased levels of active Tregs, functional Tregs, TR1, IL-10-producing functional Bregs, and IL-10-producing classical monocytes, along with decreased counts of Bregs and plasma cells. With respect to the proinflammatory immune response, peripheral levels of Th1 IFN-γ+ cells were decreased in treated PD patients, whilst the levels of CD4+ TBET+ cells, HLA-DR+ intermediate monocytes, IL-6, and IL-4 were increased after a 1-year follow-up. Our main finding was an increased regulatory T cell response after a 1-year follow-up and its link with clinical improvement in PD patients. In conclusion, after a 1-year follow-up, PD patients exhibited increased levels of regulatory populations, which correlated with clinical improvement. However, a persistent inflammatory environment and active immune response were observed.

Immunomodulation as a treatment for parkinson's disease in current trials: a systematic review and meta-analysis.

Background: Immunomodulatory drugs and immunotherapies are being evaluated in clinical trials for the treatment of neuroinflammation, as the latter is an essential mechanism for the development and progression of Parkinson's disease. Objective: The objective of the study is to review recent evidence on the evaluation of immunomodulators in randomized controlled clinical trials measuring improvement of motor symptoms. Methods: A meta-analysis of Movement Disorder Society-Unified Parkinson's disease Rating Scale (MDS-UPDRS III) scores extracted from seven articles selected after an online search of PubMed, Cochrane Library, and Clarivate's Web of Science for randomized controlled clinical trials published between 2000 and July 2023 was performed. The selected articles reported clinical trials evaluating the effects of specific immunomodulators or treatments with known effects on the immune system and inflammation. MDS-UPDRS III scores were reported in these studies, and the results of the placebo groups were compared with those of the treatment groups. Results: A total of 590 patients treated with immunomodulators and 622 patients treated with placebo were included. A test for heterogeneity yielded an I2 value > 50%. The mean standard difference for change in MDS-UPDR III score was -0.46 (CI [95%] = -0.90 - -0.02, p < 0.01). No significant differences were found in the change in mean MDS-UPDR III score between the treatment and placebo groups; however, two studies showed a trend toward separation from the mean. Conclusion: The immunomodulatory treatments included in this study showed no efficacy in improving motor symptoms in Parkinson's disease patients. Further clinical trials with larger patient populations are needed.

Characterization of excretory/secretory products of the Taenia crassiceps cysticercus involved in the induction of regulatory T cells in vivo.

The ability to modulate the host immune response has allowed some parasites to establish themselves in the tissues of an immunocompetent organism. While some parasite excretion/secretion products (ESPs) were recently reported to induce differentiation of regulatory T cells (Tregs), their identity is not known. This work is aimed to identify and characterize ESPs of Taenia crassiceps cysticerci linked with Treg induction in vivo. ESPs were obtained from cultures of T. crassiceps cysticerci and inoculated in mice, measuring Treg levels by flow cytometry. Proteins in ESPs were analyzed by electrophoresis; then, ESPs were classified as either differential or conserved. Differentially included proteins were MS-sequenced and functionally characterized. Only 4 of 10 ESPs induced Tregs. Proteins with catalytic activity and those involved in immunological processes predominated, supporting the idea that these molecules could play an important role in the induction of Tregs.

Meta-analysis to Implement Alpha-Synuclein in Extracellular Vesicles as a Potential Biomarker for Parkinsons Disease.

Background: In Parkinson's disease (PD), exosomes carry α-synuclein (α-syn), a fibrillar protein aggregates with potential value as a biomarker. Objective: Evidence on blood levels of exosomal α-syn in PD patients and controls was reviewed for their consistency. Methods: Thirty-six studies on exosomal α-syn concentrations in PD were identified in a systematic literature search and meta-analysis. Results: Both raw and ratio-adjusted blood exosomal α-syn levels were consistently higher in PD patients than in controls. The standardized mean difference (SMD) was 1.54 (0.18-2.90, CI95%, p < 0.01) and 1.53 (0.23-2.83, CI95%, p < 0.01), respectively. Conclusion: Our results suggest that exosomal α-syn concentrations could be a useful biomarker for PD.

Increased Tc17 cell levels and imbalance of naïve/effector immune response in Parkinson's disease patients in a two-year follow-up: a case control study.

BACKGROUND: Neuroinflammation has been proved to play a role in dopaminergic neuronal death in Parkinson's disease (PD). This link highlights the relevance of the immune response in the progression of the disease. However, little is known about the impact of peripheral immune response on the disease. This study is aimed to evaluate how immune cell populations change in untreated PD patients followed-up for 2 years. METHODS: Thirty-two patients with no previous treatment (PD-0 yr) and twenty-two healthy subjects (controls) were included in the study. PD patients were sampled 1 and 2 years after the start of the treatment. CD4 T cells (naïve/central memory, effector, and activated), CD8 T cells (activated, central memory, effector memory, NKT, Tc1, Tc2, and Tc17), and B cells (activated, plasma, and Lip-AP) were characterized by flow cytometry. RESULTS: We observed decreased levels of naïve/central memory CD4 and CD8 T cells, Tc1, Tc2, NKT, and plasma cells, and increased levels of effector T cells, activated T cells, and Tc17. CONCLUSIONS: PD patients treated for 2 years showed an imbalance in the naive/effector immune response. Naïve and effector cell levels were associated with clinical deterioration. These populations are also correlated to aging. On the other hand, higher Tc17 levels suggest an increased inflammatory response, which may impact the progression of the disease. Our results highlight the relevant effect of treatment on the immune response, which could improve our management of the disease.

Unveiling the social performance of selected agri-food chains in Costa Rica: the case of green coffee, raw milk and leafy vegetables.

PURPOSE: Several frameworks coincide in the importance of addressing social impacts to ensure sustainability. However, the agri-food sector, regarded as key in sustainable production, still neglects to identify potential social impacts when applying life cycle approaches. This work contributes to understanding the social performance of three agricultural products from a Latin American and Caribbean developing country as Costa Rica while recognising the challenges of Social-Life Cycle Assessment (S-LCA) application in this context. METHODS: S-LCA represents a powerful technique to evaluate the potential social impacts of a product. Three case studies were analysed through S-LCA, using the subcategory assessment method (SAM) to characterise the social impacts and detect hotspots in the production of green coffee, raw milk and leafy vegetables. Primary data was collected through questionnaires to relevant informants and observations. In addition to secondary information, these data and information were used to assess eight impact subcategories for the farmer and worker stakeholder groups and nine subcategories for the local community. RESULTS AND DISCUSSION: The main results suggest that the Costa Rican institutional and market frameworks provide an enabling environment for a generally positive social performance in the studied cases. The assessed stakeholders can fulfil basic needs through access to inputs and services and achieve fair-trading conditions. Child labour, forced labour and evidence of environmental or health risks for the surrounding communities were absent. Important efforts to address the delocalisation, migration and child labour were observed, suggesting the potential development of social handprints in further studies. However, the farm production phase, related to farmers and workers, entails hotspots regarding social security and women's empowerment. Moreover, farmers appear as the most vulnerable group because of their overall social performance. CONCLUSIONS: S-LCA helped identify relevant areas of intervention in the context of these particular case studies; however, further research and capacity building are recommended to tackle the detected challenges, both in the agri-food chains and in the use of S-LCA. Furthermore, these findings can aid in future decision and policy-making to improve and safeguard the positive social performance observed in the studied products. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11367-021-01964-4.

Regulatory impairment in untreated Parkinson's disease is not restricted to Tregs: other regulatory populations are also involved.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Various studies have suggested that the immune response plays a key role in this pathology. While a predominantly pro-inflammatory peripheral immune response has been reported in treated and untreated PD patients, the study of the role of the regulatory immune response has been restricted to regulatory T cells. Other immune suppressive populations have been described recently, but their role in PD is still unknown. This study was designed to analyze the pro and anti-inflammatory immune response in untreated PD patients, with emphasis on the regulatory response. METHODS: Thirty-two PD untreated patients and 20 healthy individuals were included in this study. Peripheral regulatory cells (CD4+Tregs, Bregs, CD8+Tregs, and tolerogenic dendritic cells), pro-inflammatory cells (Th1, Th2, and Th17 cells; active dendritic cells), and classical, intermediate, and non-classical monocytes were characterized by flow cytometry. Plasmatic levels of TNF-α, IFN-γ, IL-6, GM-CSF, IL-12p70, IL-4, IL-13, IL-17α, IL-1ß, IL-10, TGF-ß, and IL-35 were determined by ELISA. RESULTS: Decreased levels of suppressor Tregs, active Tregs, Tr1 cells, IL-10-producer CD8regs, and tolerogenic PD-L1+ dendritic cells were observed. With respect to the pro-inflammatory response, a decrease in IL-17-α and an increase in IL-13 levels were observed. CONCLUSION: A decrease in the levels of regulatory cell subpopulations in untreated PD patients is reported for the first time in this work. These results suggest that PD patients may exhibit a deficient suppression of the pro-inflammatory response, which could contribute to the pathophysiology of the disease.

Expression of Dopamine Receptors in Immune Regulatory Cells.

OBJECTIVE: Parkinson's disease (PD) patients are usually treated with L-dopa and/or dopaminergic agonists, which act by binding five types of dopaminergic receptors (DRD1-DRD5). Peripheral immune cells are known to express dopamine receptors on their membrane surface, and therefore they could be directly affected by the treatment. Regulatory cells are the main modulators of inflammation, but it is not clear whether dopaminergic treatment could affect their functions. While only regulatory T cells (Tregs) have been proved to express dopamine receptors, it is not known whether other regulatory cells such as CD8regs, regulatory B cells (Bregs), tolerogenic dendritic cells, and intermediate monocytes also express them. METHODS: The expression of dopamine receptors in Tregs, CD8regs, Bregs, tolerogenic dendritic cells, and intermediate monocytes was herein evaluated. cDNA from 11 PD patients and 9 control subjects was obtained and analyzed. RESULTS: All regulatory cell populations expressed the genes coding for dopamine receptors, and this expression was further corroborated by flow cytometry. These findings may allow us to propose regulatory populations as possible targets for PD treatment. CONCLUSIONS: This study opens new paths to deepen our understanding on the effect of PD treatment on the cells of the regulatory immune response.

Treatment-Resistant Human Extraparenchymal Neurocysticercosis: An Immune-Inflammatory Approach to Cysticidal Treatment Outcome.

OBJECTIVE: The aim of this study is to analyze the immune-endocrine profile in neurocysticercosis (NC) patients resistant to cysticidal treatment. METHODS: The inflammatory and regulatory responses of 8 resistant NC patients with extraparenchymal parasites and 5 healthy controls were evaluated through flow cytometry. Serum interleukin levels were measured by ELISA and catecholamines levels by high performance liquid chromatography. RESULTS: Higher percentages of Tr1, CD4+CD25+FOXP3+CD127- and CD4+CD45RO+FOXP3HI were found in NC patients compared with healthy controls, but no difference was found in catecholamine levels. Antigen-specific proliferative immune response was observed in NC patients. Neither anti-inflammatory nor pro-inflammatory cytokines showed differences between patients and controls, but IL-6 levels were lower in treatment-resistant NC patients. In addition, TGFß showed a significant negative correlation with dopamine. CONCLUSIONS: Altogether, these results may point to a modulation of the neuroinflammation in these patients that could indirectly favor cysticercal survival in CNS microenvironment.

Feasibility and results of an intraarterial chemotherapy program for the conservative treatment of retinoblastoma in Argentina.

BACKGROUND: The feasibility and results of intraarterial chemotherapy, also termed ophthalmic artery chemosurgery (OAC), for retinoblastoma in less developed countries have seldom been reported. PROCEDURE: A retrospective evaluation of a program of OAC in Argentina from 2010 to 2015. RESULTS: Ninety-seven eyes from 81 patients (61 bilateral) were analyzed. In 35 eyes, OAC was given as primary therapy and in 62 it was used for the treatment of tumors with partial response or those relapsing after systemic chemoreduction with focal therapy or external-beam radiotherapy. Twenty-two primarily treated eyes had group D and 13 groups B/C. A total of 400 procedures were carried out. Chemotherapy used included combinations of melphalan, carboplatin, and topotecan. There was no mortality associated with OAC. Toxicity included fever and neutropenia in five (1.25%), hypotension and bradycardia during anesthesia in two and femoral thrombosis in one, eyelid edema in nine, and neutropenia or thrombocytopenia in 28 cycles. With a median follow-up of 48.7 months (range 12-79), the 3-year probability of event-free survival (pEFS) (enucleation and/or radiotherapy were considered events) was comparable for patients who received first-line therapy and those treated at relapse (0.65 vs. 0.63, P = 0.5). In the former, the pEFS was 0.91 and 0.43 for groups B/C and D, respectively (P = 0.01). Two patients died of extraocular dissemination after refusal of enucleation. CONCLUSIONS: OAC was feasible with low toxicity. pEFS improved in all groups compared to the previous experience with systemic chemotherapy reducing the use of radiotherapy. The overall mortality associated with OAC is comparable to our previous experience with systemic chemoreduction.

Understanding host-parasite relationship: the immune central nervous system microenvironment and its effect on brain infections.

The central nervous system (CNS) has been recognized as an immunologically specialized microenvironment, where immune surveillance takes a distinctive character, and where delicate neuronal networks are sustained by anti-inflammatory factors that maintain local homeostasis. However, when a foreign agent such as a parasite establishes in the CNS, a set of immune defences is mounted and several immune molecules are released to promote an array of responses, which ultimately would control the infection and associated damage. Instead, a host-parasite relationship is established, in the context of which a close biochemical coevolution and communication at all organization levels between two complex organisms have developed. The ability of the parasite to establish in its host is associated with several evasion mechanisms to the immune response and its capacity for exploiting host-derived molecules. In this context, the CNS is deeply involved in modulating immune functions, either protective or pathogenic, and possibly in parasitic activity as well, via interactions with evolutionarily conserved molecules such as growth factors, neuropeptides and hormones. This review presents available evidence on some examples of CNS parasitic infections inducing different morbi-mortality grades in low- or middle-income countries, to illustrate how the CNS microenvironment affect pathogen establishment, growth, survival and reproduction in immunocompetent hosts. A better understanding of the influence of the CNS microenvironment on neuroinfections may provide relevant insights into the mechanisms underlying these pathologies.

A comprehensive care program achieves high remission rates in rheumatoid arthritis in a middle-income setting. Experience of a Center of Excellence in Colombia.

Management of rheumatoid arthritis (RA) in many Latin-American countries is impaired by fragmentation and scarce healthcare provision, resulting in obstacles to access, diagnosis, and treatment, and consequently in poor health outcomes. The aim of this study is to propose a comprehensive care program as a model to provide healthcare to RA patients receiving synthetic DMARDs in a Colombian setting by describing the model and its results. Health outcomes were prospectively collected in all patients entering the program. By protocol, patients are followed up during 24 months using a treat-to-target strategy with a patient-centered care (PCC) model, meaning that a patient should be seen by rheumatologist, physical and occupational therapist, physiatrist, nutritionist and psychologist, at least three times a year according to disease activity by DAS28. Otherwise, patients receive standard therapy. The incidence of remission and low disease activity (LDA) was calculated by periods of follow-up. A total of 968 patients entered the program from January 2015 to December 2016; 80.2% were women. At baseline, 41% of patients were in remission, 17% in LDA and 42% in MDS/SDA. At 24 months of follow-up, 66% were in remission, 18% in LDA and only 16% in MDS/SDA. Regarding DAS28, the mean at the beginning of the time analysis was 3.1 (SD 1.0) and after 24 months it was 2.4 (SD 0.7), showing a statistically significant improvement (p < 0.001). In all patients, the reduction of disease activity was 65% (95% CI, 58-71). Patients entering the PCC program benefited from a global improvement in disease activity in terms of DAS28.

Quantification of stiffness measurement errors in resonant ultrasound spectroscopy of human cortical bone.

Resonant ultrasound spectroscopy (RUS) is the state-of-the-art method used to investigate the elastic properties of anisotropic solids. Recently, RUS was applied to measure human cortical bone, an anisotropic material with low Q-factor (20), which is challenging due to the difficulty in retrieving resonant frequencies. Determining the precision of the estimated stiffness constants is not straightforward because RUS is an indirect method involving minimizing the distance between measured and calculated resonant frequencies using a model. This work was motivated by the need to quantify the errors on stiffness constants due to different error sources in RUS, including uncertainties on the resonant frequencies and specimen dimensions and imperfect rectangular parallelepiped (RP) specimen geometry. The errors were first investigated using Monte Carlo simulations with typical uncertainty values of experimentally measured resonant frequencies and dimensions assuming a perfect RP geometry. Second, the exact specimen geometry of a set of bone specimens were recorded by synchrotron radiation micro-computed tomography. Then, a "virtual" RUS experiment is proposed to quantify the errors induced by imperfect geometry. Results show that for a bone specimen of ∼1° perpendicularity and parallelism errors, an accuracy of a few percent ( <6.2%) for all the stiffness constants and engineering moduli is achievable.

Transient Elastography to Assess the Cervical Ripening during Pregnancy: A Preliminary Study.

Purpose To explore the feasibility of transient elastography (TE) to quantify cervical stiffness changes during normal pregnancy and its spatial variability. Materials and Methods TE was used to quantify the cervical stiffness in four anatomical regions. 42 women between 17 and 43 years of age and at 6 - 41 weeks of gestation were studied. The stiffness was related to gestational age at the time of examination, interval from ultrasound examination to delivery and cervical length to evaluate the potential of TE to assess cervical ripening. In addition, a sensitivity analysis based on Cronbach's alpha coefficient was carried out to assess the concordance between inter/intra-operator measurements. Results There were significant correlations between cervical stiffness measured in the four regions with gestational age and the remaining time for delivery. Results confirm stiffness variability within the cervix. No significant association was found between cervical length and stiffness in the four ROIs. Associations between gestational age and remaining time for delivery with cervical length present weaker correlations than with cervical stiffness. The external part of the cervix was significantly softer than the internal one, and these stiffness values vary significantly in the anterior compared to the posterior cervix. The measurements taken by the same and by two different observers for different regions in the cervix were reliable and reproducible. Conclusion It is feasible to objectively quantify the decrease of cervical stiffness correlated to gestational age. Transient elastography is a valuable promising tool to provide additional information on the process of cervical effacement to that obtained from digital examination and conventional ultrasound. Further studies are needed to assess the feasibility of the technique in obstetric clinical applications, such as prediction of preterm birth or success in labor induction.

[Omental hernia through esophageal hiatus simulates mediastinal lipomatous tumor]. / Hernia omental a través de hiato esofâgico que imita tumor lipomatoso mediastinal.

Omental hernia through the esophageal hiatus is extemely infrequent. Paraesophageal hiatal hernia with omentum in the herniary sac mimics a mediastinal lipomatous tumor and differential diagnosis should be made. This diagnosis requires experience and knowledge of the differences between these two pathologies. In the following study we describe the case of an omental hernia and the characteristics that make it different from other pathologies.

Anti-Candida activity and biocompatibility of silver nanoparticles associated with denture glaze: a new approach to the management of denture stomatitis.

The association of silver nanoparticles (AgNps) to sealant agent Palaseal® can be a promising alternative for complete denture wearers who may develop denture stomatitis (DS). The study aimed to evaluate the anti-Candida and biocompatible potential of silver nanoparticles synthesized by three routes associated with denture glaze to prevent and/or treat oral candidiasis. Surface acrylic resin specimens were treated with different associations of glaze with AgNps (VER+AgUV, VER+AgTurk and VER+AgGm). As controls, specimens were treated with glaze+nystatin (VER+Nyst), glaze only (VER) or submerged in PBS (PBS). Afterwards, Candida albicans biofilm was developed for 24 h, 15 d and 30 d. Subsequently, the biofilm was quantified by CFU/mL, XTT assay and confocal laser scanning microscopy. Fibroblasts were submitted to conditioned medium with the same associations for 24, 48 and 72 h and LIVE/DEAD® viability test was carried out. Regardless of the period, there was a significant reduction (p < 0.01) of viable fungal cells load, as well as inhibition of fungal metabolic activity, in specimens treated with glaze+AgNps associations, compared to VER and PBS. The anti-Candida effects of the associations were similar to the VER+Nyst group, with emphasis on VER+AgGm, which showed the highest percentage values of non-viable fungal cells maintained over time. The associations did not prove toxicity to fibroblasts. The AgNps exerted antimicrobial activity against C. albicans biofilms and are biocompatible. The most effective results were achieved with the association of glaze+silver nanoparticles synthesized by the green chemistry method (AgGm), proving to be an innovative alternative in the management of DS.

Progressive Supranuclear Palsy Syndrome: An Overview.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease, commonly observed as a movement disorder in the group of parkinsonian diseases. The term PSP usually refers to PSP-Richardson's syndrome (PSP-RS), the most typical clinical presentation. However, the broad concept of progressive supranuclear palsy syndrome (PSP-S) applies to a set of clinical entities that share a pathophysiological origin and some symptoms. According to its clinical predominance, PSP-S is divided into subtypes. PSP-S has clinical similarities with Parkinson's disease, and both pathologies are classified in the group of parkinsonisms, but they do not share pathophysiological traits. By contrast, the pathophysiology of corticobasal syndrome (CBS) depends on tau expression and shares similarities with PSP-S in both pathophysiology and clinical picture. An involvement of the immune system has been proposed as a cause of neurodegeneration. The role of neuroinflammation in PSP-S has been studied by neuroimaging, among other methods. As it is the case in other neurodegenerative pathologies, microglial cells have been attributed a major role in PSP-S. While various studies have explored the detection and use of possible inflammatory biomarkers in PSP-S, no significant advances have been made in this regard. This review is aimed at highlighting the most relevant information on neuroinflammation and peripheral inflammation in the development and progression of PSP-S, to lay the groundwork for further research on the pathophysiology, potential biomarkers, and therapeutic strategies for PSP-S.

Cardiac ultrasound simulation for autonomous ultrasound navigation.

Introduction: Ultrasound is well-established as an imaging modality for diagnostic and interventional purposes. However, the image quality varies with operator skills as acquiring and interpreting ultrasound images requires extensive training due to the imaging artefacts, the range of acquisition parameters and the variability of patient anatomies. Automating the image acquisition task could improve acquisition reproducibility and quality but training such an algorithm requires large amounts of navigation data, not saved in routine examinations. Methods: We propose a method to generate large amounts of ultrasound images from other modalities and from arbitrary positions, such that this pipeline can later be used by learning algorithms for navigation. We present a novel simulation pipeline which uses segmentations from other modalities, an optimized volumetric data representation and GPU-accelerated Monte Carlo path tracing to generate view-dependent and patient-specific ultrasound images. Results: We extensively validate the correctness of our pipeline with a phantom experiment, where structures' sizes, contrast and speckle noise properties are assessed. Furthermore, we demonstrate its usability to train neural networks for navigation in an echocardiography view classification experiment by generating synthetic images from more than 1,000 patients. Networks pre-trained with our simulations achieve significantly superior performance in settings where large real datasets are not available, especially for under-represented classes. Discussion: The proposed approach allows for fast and accurate patient-specific ultrasound image generation, and its usability for training networks for navigation-related tasks is demonstrated.

Cabozantinib Plus Nivolumab in Patients with Non-Clear Cell Renal Cell Carcinoma: Updated Results from a Phase 2 Trial.

Treatment options are limited for patients with non-clear cell renal cell carcinoma (nccRCC). Patients with nccRCC experienced a favorable objective response rate (ORR) in a phase 2 trial of cabozantinib plus nivolumab. We now report updated efficacy and safety results at median follow-up of 34 mo for patients with papillary, unclassified, or translocation-associated RCC. Cabozantinib and nivolumab were administered at standard doses to patients with metastatic nccRCC that had progressed on zero or one line of systemic therapy. The primary endpoint was the ORR according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Forty patients were treated. At median follow-up of 34 mo for survivors, the ORR was 48% (95% confidence interval [CI] 31.5-63.9%). Median PFS was 13 mo (95% CI 7-16); the 12-mo and 24-mo PFS rates were 51% (95% CI 34-65%) and 23% (95% CI 11-37%), respectively. Median OS was 28 mo (95% CI 23-43); the 18-mo and 36-mo OS rates were 70% (95% CI 53-82%) and 44% (95% CI 28-60%), respectively. No new safety signals were seen with cabozantinib and nivolumab. This extended follow-up analysis demonstrates promising efficacy, and highlights the potential for sustained responses with cabozantinib plus nivolumab in patients with metastatic nccRCC.